In the Mists of a Fungal Metabolite: An Unexpected Reaction of 2,4,5-Trimethoxyphenylglyoxylic Acid

Abstract

The reactions of phenylglyoxylic acids during the synthesis and biological evaluation of fungal metabolites led to the discovery of hitherto unknown compounds with a p-quinone methide (p-QM) structure. The formation of these p-QMs using 13 C-labelled starting materials revealed a key-step of this reaction being a retro-Friedel-Crafts alkylation.Molecules 2020, 25, 1978 2 of 15 catechol estrogen-o-quinones [11][12][13]. They are well known intermediates in the biosynthesis of natural products. Their high reactivity and potential has also been exploited in the total synthesis of some natural products such as the flavonoids rugaurone A-C [14] cherylline [15] and 20-deoxy-elansolid B1 [16]. Furthermore, the reactions of p-QMs have extensively been studied to generate compounds of pharmaceutical interest [17][18][19][20] and quite recently they were used as starting materials for an organo-catalytic asymmetric α-alkylation of aldehydes [21].During our research on metabolites from fungi and lichens we came across the chemical properties and reactions of phenylglyoxylic acids [22]. Thereby, we encountered several unexpected and unprecedented reactions yielding 3,3-diaryl substituted benzofuranones which undergo retro-Friedel-Crafts alkylation in hydrochloric acid forming the p-QM structure. These molecules are similar to 3,3-diaryloxoindoles and 3,3-substituted oxoindoles that have lately been studied quite extensively yielding pharmacological interesting molecules [23][24][25][26][27][28]; they are also known intermediates from isatines and a prominent motif in natural product products, as for example in azonazine [29]. In contrast to isatines, benzofuran-2,3-diones are widely overlooked [28,30]. This was another reason to provide an access to this rare structural motif. Results and DiscussionOxidation of 2,4,5-trimethoxy-acetophenone (1, Scheme 1) with SeO 2 [31] gave 2,4,5trimethoxyphenylglyoxylic acid (2); this compound has previously been isolated from the fungus Polyporus tumulosus Cooke [22,32]. As an alternative, a Friedel-Crafts acylation of 2,4,5-trimethoxybenzene (3) in the presence of TiCl 4 gave a 94% yield of ester 4 [33-35] whose hydrolysis with methanolic KOH for 2 h resulted in an almost quantitative yield of 2. Partial deprotection of the methoxy-groups with AlCl 3 of 2 yielded 5 albeit in low yields, while demethylation with either hydrobromic or hydrochloric acid yielded 6, a red colored solid in almost quantitative yield. A major issue in these reactions is the instability of the α-keto-acids that are readily decarboxylated [22,36]. These findings parallel previous reports for trimethoxy-substituted aromatic compounds [36]. Furthermore, α-keto acids were used for the synthesis of oxadiazolopyrazines-selective antibacterial agents against Haemophilus influenzae [37]. Attempts to cyclize 5 under a variety of different conditions invariably led to the formation of 6 in moderate to excellent yields. The formation of 7 was only observed to a rather minor extend by ESI-MS.